RT Journal Article
T1 Met signaling in cardiomyocytes is required for normal cardiac function in adult mice
A1 Arechedera, María
A1 Carmona-Mejías, Rita María
A1 González-Núñez, María
A1 Gutiérrez-Urquiza, Álvaro
A1 Bragado, Paloma
A1 Cruz-González, Ignacio
A1 Cano, Elena
A1 Guerrero, Carmen
A1 Sánchez, Aránzazu
A1 López-Novao, José Miguel
A1 Schneider, Michael D.
A1 Maina, Flavio
A1 Muñoz-Chápuli-Oriol, Ramón
A1 Porras, Almudena
K1 Cardiología
AB Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-α-MHC mouse line (referred to as α-MHCMet-KO). Although α-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as β-MHC and ANF, was also observed. By the age of 9 months, α-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in α-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-β production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in α-MHCMet-KO mice. Consistently, we show that HGF acts through p38α to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.
PB Elsevier
YR 2013
FD 2013-12
LK https://hdl.handle.net/10630/36300
UL https://hdl.handle.net/10630/36300
LA eng
NO María Arechederra, Rita Carmona, María González-Nuñez, Álvaro Gutiérrez-Uzquiza, Paloma Bragado, Ignacio Cruz-González, Elena Cano, Carmen Guerrero, Aránzazu Sánchez, José Miguel López-Novoa, Michael D. Schneider, Flavio Maina, Ramón Muñoz-Chápuli, Almudena Porras, Met signaling in cardiomyocytes is required for normal cardiac function in adult mice, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1832, Issue 12, 2013, Pages 2204-2215, ISSN 0925-4439, https://doi.org/10.1016/j.bbadis.2013.08.008
NO This work was supported by grants: (AFM)-13683 from Association Française contre les myopathies, France, FIS-PI07/0071 and SAF-2010-20198-C02-01 from Ministry of Science and Innovation, Spain, and grants from Comunidad de Madrid/Universidad Complutense de Madrid: CAM/UCM 920384 and UCM-BSCH 920384, Spain to A.P.; BFU2011-25304 from Ministry of Science and Innovation, Spain, RD12/0019/0022 (TerCel network, ISCIII), P11-CTS-7564 (Junta de Andalucía) to R. M.-Ch.; FRM (Fondation pour la Recherche Médicale), Fondation Bettencourt-Schueller, and Association Française contre les myopathies (AFM) to F.M.; SAF2010-15881 from Ministry of Science and Innovation, Spain, and RD012/0021 (RedinRen network, ISCIII), and GR100 (Junta de Castilla y León) to J.M. L.-N.
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026